Effect of Food on the Oral Bioavailability of Didanosine from Encapsulated Enteric‐Coated Beads

The objective of this study was to assess the effect of food and timing of meals on the bioavailability of didanosine from encapsulated enteric‐coated beads. Four different independent, open‐label, single‐dose, randomized, crossover studies were conducted in healthy subjects (n = 20–30). Didanosine (400 mg) was given concomitantly with a high‐fat meal, light meal, yogurt, and applesauce. In addition, didanosine was given 1, 1.5, 2, and 3 hours before and 2 hours after a light meal. Statistical comparison with fasting conditions was made using the equivalence approach for Cmax (70%‐143%) and AUC (80%‐125%). The high‐fat meal, light meal, yogurt, and applesauce decreased the Cmax by 46%, 22%, 30%, and 24%, respectively, and lowered the AUC by 19%, 27%, 20%, and 18%, respectively; statistical analyses indicated an indeterminate food effect, except for the Cmax for the high‐fat meal. For 1 hour before meal, Cmax and AUC were lower by 15% and 24% and, for 2 hours after meal, were lower by 15% and 10%, respectively. There was an indeterminate food effect for 1 hour before the meal treatment; in addition, 2 hours after the meal, treatment approached statistical equivalence, missing narrowly on the lower bounds. For 1.5, 2, and 3 hours before meal treatments, Cmax values were unchanged, but AUC was lower by 10%, 4%, and 0%, respectively; lack of food effect was observed for all three treatments. Across studies, median time to Cmax ranged from 1.67 to 2.67 hours but was delayed by 2.5 to 3 hours with high‐fat and light meals compared to fasting conditions. The half‐life of didanosine was 1.5 to 2 hours. It was concluded that the bioavailability of didanosine from encapsulated enteric‐coated beads was reduced by approximately 20% to 25% with food, which can be circumvented by taking didanosine on an empty stomach. The clinical significance of such moderate reductions in didanosine exposure with food, especially as part of a highly active antiretroviral therapy, is not clear.